The present invention relates to the medical therapy of established cancers on and throughout the animal and human body by causing cell-death by reprogramming intra-cellular communication systems so that they fail by apoptosis. Most particularly, the invention relates to the use of an electronic system that is capable of reaching, detecting and recording intra-cellular analog signals of cancer cells that are organized or formed into islands or clusters of malignancy. Then the cellular signals are reprogrammed for rebroadcast or transmission into the cancer to damage and disable the cell process or cause the cell process to trigger apoptosis (programmed cell death).
This invention is an improvement of the invention disclosed in co-pending International Application No. PCT/US2009/030701, filed Jan. 12, 2009, the disclosure of which is incorporated herein by reference.
All humans and animals are constructed of cells. Cells are the smallest fundamental unit of life. A cell is the smallest living structure capable of performing all of the processes that define life. All cells have electrical and chemical processes. Most cells have also an electrical communication system to operate the cell. The human body is made up of some 100 trillion cells representing perhaps some 300 cell-types. Each cell-type performs a specific function such as operating muscles, glands and vital organs. In addition, nerves, which are made of communicating cells called neurons, provide electrical regulating signals to operate and adjust enormous amounts of functional activities throughout the body to maintain homeostasis (life equilibrium).
Normal cells reproduce by going through a cell cycle that leads to reproduction of similar cells by a process of mitosis which is where a single cell divides and then splits into two daughter cells that are exact replications of the mother cell. Normal cells are limited as to how many times they can reproduce by mitosis. Cancer cells, on the otherhand, reproduce rapidly throughout their life, some at the rate of a complete mitosis every half hour.
A characteristic cell, such as that depicted in FIG. 1, is surrounded by a thin plasma membrane which separates the internal structures and operating organelles from the cells external environment. A portion of that membrane is shown in FIG. 2, in greatly enlarged fashion. It houses and protects the contents of the cell. It consists of a bilayer of phospholipids and various proteins which are attached or embedded.
The plasma membrane is a semipermeable structure that allows passage of nutrients, ions, water and other materials into the cell. It also allows an exit pathway for waste products and for functional two-way passage of many kinds of molecules to adjust cell chemistry. The principal purpose of the cell membrane is to provide a barrier that contains all of the processes and components within the living cell and to simultaneously repel unwanted substances from invading or entering the cell.
Since cells are electrochemical in nature, the plasma membrane is the site for generating the cells' electrical signals for metabolic and other operations and to serve as a means to communicate, relay and receive signals with other cells, especially those of similar type. The nucleus and plasma membrane communicate with electrical signals. The nucleus determines how the cell functions and also determines the architecture of the cell and its contents. The plasma membrane can use electrical signaling to open passageways and ion channels to allow the intake of chemicals as well as the outflow of cellular waste products.
The cell membrane is coated with a relatively thick glycocalyx, which is designed and produced by the cell to protect it and allow it to be recognized. The nucleus has input into the crafting of membrane defensive characteristics. The glycocalyx can produce a negative electric surface charge in cancer cells so as to repel the body immune system.
The cell membrane regulates the flow of materials into and out of the cell. Also it can detect external signals and mediate interactions between other cells. Membrane carbohydrates installed on the outer surface function as cell markers to allow a cell to distinguish itself from other cells.
The plasma membrane contains the sites where the electrical energy is created and the cellular communication signals are formed. These signals are transmitted over the cytoskeleton, which acts like wires, to regulate and trigger metabolic and functional processes within the cell.
The cytoskeleton, a portion of which is shown in enlarged fashion in FIG. 3, maintains the shape of all cells from the inside. It is like a geodesic structure that provides strength and internal areas for electro-chemical timed reactions. Noteworthy is that the cytoskeleton extends with intermediate filaments into other cells and links up with their cytoskeleton (see FIG. 4B) to maintain and form communication links into adjacent cells. The cytoskeleton structure is made up of a network of hollow-microtubules, solid-microfilaments and solid-intermediate filaments. The cytoskeleton is anchored to the plasma membrane and serves as the “wiring” to transmit the cellular communication signals.
The cytoskeleton is made up of actin and myosin which are also found in muscle structures. The cytoskeleton also controls the circulation of the cytosol which is the fluid and semi-fluid that suspends the organelles. Organelles are the functioning entities of the cell that manufacture and distribute cellular products and processes necessary for the cell to live.
Individual cells operate themselves by electrical and chemical processes to maintain life and to perform the function for which a given cell has been constructed. Cancer cells have different electrical signals than normal cells.
Cells generate their electrical energy and communication signals within the plasma membrane. Such membrane also has electrical connections to adjacent cells of the same type to allow uniform information transfer.
As shown in FIGS. 4A-4D, cell communication is both electrical and chemical. Little scientific work has been done to understand electrical cell signals, due largely to the lack of electronic equipment to detect, record and retransmit the tiny cellular waveforms.
The following is useful terminology for cytoplasm and key cellular organelles:
Cytoplasm and Nucleus: The cytoplasm, a fluid which can be rather gel-like, surrounds the nucleus, which is considered an organelle. The nucleus contains the DNA genetic information and hence controls both the activity of the cell and its structural nature. As shown in FIG. 1, the nucleus is spherical and is surrounded by a double membrane, the nuclear membrane and envelope, which is perforated by a significant number of pores that allow the exchange of materials and substances with the cytoplasm.
Mitochondria: An important organelle is the mitochondria which serves as the power station for the cell. They are rod or oval shaped structures functioning as respiration for the cell. A number of mitochondria are scattered within the cytoplasm and move in accordance with its flow, as shown in FIGS. 1 and 3. The product produced as a biological fuel is called adenosine tri-phosphate (ATP). The manufacture of ATP results from the processing of proteins, fats and carbohydrates. The cell communication system supplies the ATP to other organelles that require this bio-fuel to provide processing energy, as needed.
Endoplasmic Reticulum (ER): The ER is a network of membranes that forms channels that criss-crosses the cytoplasm utilizing its tubular and vesicular structures to manufacture various molecules. The system is doted with small granular structures called ribosomes for the synthesis of proteins. Smooth ER makes fat compounds and deactivates certain chemicals like alcohol or detected undesirable chemicals such as pesticides. Rough ER makes and modifies proteins and stores them until notified by the cell communication system to send them to organelles that require the substances. All cells in humans, except erythrocytes (red blood cells), are equipped with endoplasmic reticulum.
Golgi Apparatus: The Golgi apparatus consist of Golgi bodies which are located close to the nucleus and consist of flattened membranes stacked atop one another like a stack of coins. The Golgi apparatus sorts and modifies proteins and fats made by the ER, after which it surrounds and packs them in a membranous vesicle so they can be moved around the cell, as needed. Similarly there is a process to pack up cell waste products for expulsion from the cell via ports in the plasma membrane into the extra cellular spaces.
Lysosomes: Lysosomes are the digestive system for the cell. They contain copious quantities of acids, enzymes and phosphates to break down microbes and other undesirable substances that have entered the cell. They also digest and recycle worn-out organelles to make new cellular structures or parts.
Ribosomes: Ribosomes are tiny spherical organelles distributed around the cell in large numbers to synthesize cell proteins. They also create amino acid chains for protein manufacture. Ribosomes are created within the nucleus at the level of the nucleolus and then released into the cytoplasm.
Cancer occurs in normal cells with birth-defected distorted chromosomes and abnormal genes which lead to the formation of a defective cell which exhibits a severe disorder of mitosis (cell division). The thrust of a cancerized cell is to continuously reproduce by splitting into similar daughter cells uncontrollably.
Cancer cells can reproduce continuously every 30 minutes. When a cell becomes malignant, changes are made in its electrical communication signals.
Once a normal but defective cell becomes cancerized it has a destiny to grow a colony of similar cancer cells without regard to its former normal cell duties and destiny. Defective normal cells that have the potential to become cancerized can be potentially triggered by a number of factors such as cigarette smoke, chemicals, viruses, radiation or other influence. A cancer cell emerges from a normal cell that has undergone a malignant change.
Cancer cells continue to reproduce by splitting (including the nucleus) into two daughter cells which themselves split and grow into adult cancer cells and then split again. This is the splitting process of mitosis that produces daughter-cells which ultimately enlarges into a massive collection of cells forming a tumor. The cells can go to other distant sites by a process called metastasis. Once this metastatic process proceeds the cancer spreads to critical body parts and usually heralds a poor overall outcome for the patient. Cancer cells are unregulated, disorganized and engage in extremely rapid rates of mitosis. When enough cancer cells are made, they form larger tumors which interfere with the duties and nutrition of nearby normal cells.
Cancer does its damage in complex ways that include strangling or distorting organs, blood vessels and nerves as well as working its way into bones, brain and muscles. Groups of cancer cells are connected together and feature an inter-connected electrical communication system internally and between each of the cells within a malignant tumor. Cancer cells perform no function that contributes to the homeostasis (life equilibrium) of the body, in any way.
Cancer cells have developed ways to repel the human body immune system by several means including erecting an electrical shield on the outer surface of the plasma membrane which is produced by the cancer cell, itself. The body's natural immune system is not effective in attacking cancer as it does in attacking invading bacteria or viruses or even malfunctioning cells that have been injured.
Although it might be thought that many cancer cells are not susceptible or capable of undertaking a programmed cell death because of the immortal nature of healthy cancer cells, that is not true. Cancer cells can be destroyed just as normal cells if they lose or experience changes in their cellular communication capability which alters their internal signaling capacity. It may be potentially possible that some healthy cancer cells may initially resist signals to confound their internal communication system. But reprogramming the treatment signals ultimately causes shut-down of the cellular electric system. It is believed that targeted cells are unable to resist the effects of reprogrammed destructive codes that are externally delivered directly into or through the plasma membrane, so the confounding treatment signal reaches the nucleus.
Cancer cells that are born significantly defective or suffer injury to DNA routinely die and are susceptible to being phagocyted and devoured by the immune system. There has been no prior art that attempted to accomplish reprogramming of the intra-cellular communication system of a cancer cell but there have been experiments to punch holes in the cell wall to allow the cytoplasm to drain out and hence kill the cell via a lysis mechanism induced by using 1.5 to 2.5 kilovolts in microsecond pulses. This, however, is a cumbersome cell-by-cell process.
Just as normal cells, cancer cells have a complex cellular wall plasma membrane which allows the passage of desired nutriments and electrolytic ions into the cell and the excretion or expulsion of waste products and certain ions from the cellular interior into the extracellular space. The passage of ions through the cellular membrane generate or create a flow of electric currents through the membrane. The cancer cell membrane is the source of the intra-cellular electrical energy that operates the signaling processes within the cell. The plasma membrane anatomy has evolved as a generator of the electrical energy which is formed into a signaling format that operates a particular cell. The signal characteristics of a cancer cell are different than found in non-malignant cells. When a cancer cell is genetically created from a normal cell the signaling process is altered to allow unlimited reproduction and the erection of a strongly negative electrical charge within the glycocalyx outer wall coating layer on the plasma membrane to protect the cancer cell from the body's own immune system.
The electrical energy generated in the plasma membrane forms signals and transfers them onto close attachments of cytoskeleton filaments. This communication energy moves around the cell via the cytoskeleton acting as both a physical support structure, a series of shelves and hooks to locate cellular processes and to serve as a sort of wire network to allow electrical signals a functional pathway. The malignant cells operations are regulated, switched on or off and combined with chemical areas to initiate electrochemical reactions. The electrical signaling energy presents a format that provides for a communication system not only within a given cell but throughout the entire tumor from one cell to others. This combined electrical flow within and between cells act like an orchestra playing in harmonies via the genetically introduced coded operational and communication signaling system. From the living cells a communication system emerges as a sort of instructional and guidance system which, among other duties, allows for the decision and instructions for selected cells to metastasize to distant sites to establish new colonies of malignant cells. The communication system also is able to signal to nearby blood vessels to generate additional or larger arteries directly into the tumor where upon smaller arterial branches will bud and bring blood with its oxygen to the parts of the tumor cluster that requires such nourishment. This process is called angiogenesis.
First and absolutely, all cells, including malignant ones, have an internal signaling mechanism to coordinate all of their life processes and therefore to remain alive. Intra-cell and cell-to-cell signaling ability exists so that similar cells can work together. An example is the coordinated electric release of adrenalin from all or most of the cells that make up the adrenal gland that sits on top of each kidney in response to a perceived fear event. A release of adrenalin happens when the eyes and/or auditory system have sensed a major danger and transmit a rapid afferent signal to the brainstem and limbic system and most especially the amygdala where fear management is centralized. Once detected as a fearsome danger, an electrical efferent signal races to the adrenal gland and signals for the excretion of adrenalin into the blood stream to bring the entire body to emergency alert status. The body is now ready to fight or to attempt an escape from the danger, all determined by the brain assessment of the potentially fearsome episode. To accomplish all of this no chemical-switching is used except for the actual manufacture and release of the adrenalin chemical stimulant, itself. Everything from sensing danger, to making a decision, to turning on adrenalin and to signal its release into the circulatory blood stream happens virtually instantaneously, all solely by electrical signals. Chemical signaling would have been too slow to respond to an imminent emergency. Because of pre-designated signal inputs and pathways, only the correct cells participated in the emergency. The neighboring kidney plays little part in the emergency. Many cells of the adrenal gland are coordinated to excrete the adrenalin simultaneously so that the correct amount was applied to alert the entire body. That takes successful cellular neuro-signaling communication between a large number of cells, doing it at blinding speed. Digestion is stopped and blood moved into muscles to provide the oxygen for power and speed and the brain's senses are focused into a highly defensive alert and all previous thoughts and activity is shut-down in order to deal with the danger.
An initiating cancer cell starts out as a normal cell but develops a chromosomal and/or a genetic chaos that drives a transformation to malignancy. Prevailing cancer theory blames mutations in important regulatory genes for disturbing the normal controls on cells that are destined to become malignant. Such theory does not give credit to the damaging changes to actual chromosomes that are seen in many cancer cells. The distorted, broken or bent chromosomes unbalance thousands of genes en masse and are sufficient to trigger cellular instability that leads to serious genetic disruption and to account for the transformation of so-called normal cells into malignant ones. The cancer cells retain their electrochemical signaling and operating systems which existed when each cell was a normal cell, but during cancerization a cancer cell rearranges its cellular mechanisms in new ways to disconnect its communication ability from adjacent normal cells and to start rapid reproduction of more cancerous cells which are then connected to communicate only within their own transformed malignant species.
Interestingly, the first cancer cells that are adjacent to normal unaffected cells are sometimes not wired into the rest of the tumor and serve as a barrier separating the rapidly forming tumor from adjacent normal cells. Potentially, these first layers of cells that undergo cancerization are only a demarcation line from malignant to normal and may not have to participate or only partially engage in communications within the cellular command and control signaling system and therefore require less communication capability. Later forming cells do develop the desmosome interconnection communication systems between adjacent cell walls and are fully involved in tumor-wide signaling.
Neither the normal cell nor the malignant cell can live without a functioning electrical signaling mechanism to operate the electro-chemical processes that are shelved in places along the cytoskeleton. The cytoskeleton provides a somewhat flexible geodesic-like framework to maintain cell shape, provides shelf space or hangers for chemical or electrochemical process and allows space for the organelles, nucleus and protein manufacturing elements within the cell. The cytoplasm provides moisture and nutriments and serves as a transport mechanism within the cell. There is a cytoplasmic streaming process that causes directional movement of the liquid or gel-like cytoplasm as a means of local transport for the semi-floating organelles (functional cell components). Likely this allows these floating structures to move about the cytoplasm to connect by some sort of communication link between non-mobile structures located and attached to the cytoskeleton. In addition, contact with the cellular membrane, nucleus and other organelles, becomes possible as they come into various close proximity positions to allow interactive signaling exchange.
The cytoskeleton is composed and constructed of the intermediate filaments which provide the internal structure to maintain cellular shape and make contact into the plasma membrane which allows for distribution of the signals that originate within said membrane. This filamentous structure serves to provide a sort of wiring system for electrical signals to travel to sites of chemical process to coordinate cell-life duties in both normal and cancerous cells. The cytoskeleton intermediate filaments are composed of compounds that are similar to the structures of muscles which have electrical properties. There is a flexibility in the cytoskeleton to take up the effect of movement that occurs throughout all multi-cellular organisms. The signals traveling via the cytoskeleton most likely initiate and stop the chemical reactions, as required. The electrical signals likely skip and travel along the surface of the filamentous network rather than within the central framework, again on some sort of scheduled or timed basis or in response to some event or instruction. The genetically produced signaling system may be thought of a sort of simplified cellular neuro-system that substitutes for a brain to operate the cell. The nucleus may harbor some sort of instructional pathways that help the cancer cell live and be a member of the overall tumor structure. The nucleus may also provide the signals that release designated cells to undertake metastasis. Access to all systems within the cell by the nucleus is made possible by electrical signal switching and transmissions to rearrange the cell duties. Signaling pathways are altered by inputs and events in what stands in for a sort of cellular intelligence.
Cells become more electro-negative in the course of cancerization, no doubt genetically mediated. Cancer cells seem to reconstruct the cellular membrane access ports to allow the importation of more sodium and sugars than non-cancerous cells of the same size. The electrical potential between the inner and exterior wall layers of the plasma membrane serve as a sort of battery or solid-state generator to supply the power to operate the individual cell including cancer cell. It is believed that during the process of cancerization there is a reprogramming within the communication system for how the cell conducts its business.
The cytoskeleton intermediate filaments are woven or hooked together at their connection points throughout the cell's interior to allow the flexing of the overall cellular structure. Importantly, as shown in FIG. 4B, the intermediate filaments continue protruding through the desmosome which allows a connection to an adjoining cancer cell. This piercing of the cell wall within the desmosome is how signals are sent and received from adjoining cells. There can be several desmosome connections on different aspects of the plasma membrane so as to connect to cells over, under and beside a given cancerous cell, so as to communicate with all. In the alternative, other types of cellular attachment for signal transduction or transmission is likely. Every cell is a unit of life unto itself and has the ability to accomplish some sort of simple primitive reasoning or organized processing as well as communication with its neighboring similar cells.
Beside being barrier cells it is believed that the non-desmosome-connected cells may became the cells that would be released to metastasize, although no one is positive of this. Some cells do not have desmosomes inter-cellular connections but are assembled by tight junctions or intermediate functional mechanisms. It is not known, if cytoskeleton connections touch the point of other types of cellular adhesion as a communication link to adjacent cells or make the transitional connecting in mid-desmosome. There is a likely expectation that all the abutting cancer cells are able to communicate with one another. But how much is communicated between cells may differ. It is suspected that cancer cells that are going to metastasize do prepare themselves to split-away from the tumor cluster. As the cell gets ready to metastasize it gets more compressible. Presumably this is a preparatory part of the process of breaking away from the tumor to travel elsewhere via the lymphatic or vascular system in order to establish a new cancer colony.
It is not known how signals go through to other cells when desmosomes connections are not in attendance. Potentially the other types of cell wall connections do at least allow for the transfer of electrical instructions such as releasing to go and metastasize or to reproduce or even to determine if enough blood supply is available throughout the tumor.
Electrical signals are believed to travel on the surface of the intermediate filaments and reach chemical processes and likely ignite or stimulate a reaction that contributes to reproduction, protein production or metabolic activity. Without electrical activity the cell could not function. Cell biologists know this but have not demonstrated an inclination or capability to address how the electrical component of cells really work. Focus has been on anatomical identification and labeling and in chemical actions and reactions that are present. Such work has been going on for more than one hundred years. The age of electronics with its ever evolving capability and capacity have made it possible to actually trace and study electrical phenomenon in cells.
Cells have electrical zones, part of which concerns the plasma membrane and part of which concerns the nucleus and other cell organelles. The cytoskeleton is connected to the inside of the cell wall and serves as a pathway to distribute electrical communications around the cell. Between the inner and outer cell wall there is an electrical membrane potential that provides clues pointing to the cellular plasma membrane as the source of electrical energy and signal formation. The components within the cell wall function as a sort of solid-state battery or analog electric generator. It can transport ions from the extracellular space into the cell and it can discharge ions and waste as required to maintain the desired properties of the cell. In cancers the charge of the glycocalyx takes on a negative defensive charge to repel the body's immune system during cancerization restructuring.
The question comes to mind as to why have cell biologists concentrated on chemical signaling for the past 100 years? With microscopes, scientists have pursued every corner of the cell, including cancer cells, to study and try to learn what was going on. They have been able to name the anatomical parts of the cell and study at least some of the chemical reactions that occurred on some of the cytoskeleton shelves. But what they have not done is determine anything about the electrical component or the contribution of an electrical signal at any given place within the cell interior. When they did not have full answers they just moved to the chemical reaction explanation, which in itself is amazing when one considers how really small a cancer cell is individually. How the complete communicational cell process fully operates remains, for all practical purposes, a mystery.
Little by little university cell researchers and teaching teams continue to study chemical reaction activity in cellular models. No actual individual cellular communication reactions that involve electricity have been completely demonstrated in the laboratory. Cellular biologists are able to analyze and identify the presence of many cytokine, ions of sodium, potassium, and calcium among others. With the presence of sodium and potassium ions one can bet there is an electrical process going on. Sodium is always involved in sparking signals that are found in all cellular signal processes. The cell is a little tiny unit of life which requires a lot of preparation and various kinds of microscopes to be able to peer into and study. Think of 60 to 400 cells occupying the space taken up by a ball point pen dot and one can imagine how difficult it is to study a single cell. In the beginning the light microscope was used by Robert Hooke during the 17th century to study cells. The electron microscope first introduced by Ernst Ruska in 1933 enabled cells to be explored at up to 50,000 times magnification. The tunneling microscope invented in 1981 by Binnig and Rohrer in IBM's Zurich laboratory has taken the idea of studying a single atom or subatomic particle into the realm of possibility and now opens up the potential for interpreting how chemicals participate with electrical signals in the electrochemical processes to form signals and reactions.
The certain reason as to why scientists have not studied cellular electricity is that there was no proper electronic equipment in existence until the 1990s that could possibly detect, record and allow transmission of these ultra-low power, analog and very fast signals to properly study their contribution to cellular processes. Since the cellular and biochemists have been so invested in the concept of chemical reactions being the communication methodology for cells, they never approached electrical activity as a partner with chemistry to operate cell life. Electrochemical process abound within operating and fast reproducing cells. All cancer cells possess electrical processes to maintain metabolism and plasma membrane operations along with enter and intra cellular communication activities. The present inventors doubt there is any healthy cancer cell that does not have an electrical process working away. Neurons have an electrical signaling process and a cellular electrical process because they are concerned with operation of body systems via the relaying of neuro-codes via nerves. Cancer cells are equipped with internal electrical operating processes that are concerned with protecting, reproducing and the operation of metabolic activity within individual cells as well as internal communication and signaling with adjacent cells. It is also possible that cancer cells are able to communicate to nearby blood vessels to encourage them to extend a new vascular connection to clusters of cancer cells to supply more oxygen and nutrition.
There is an “information minimum” required for life to function in cellular forms that “know” their environmental needs and duties. Cellular systems are completely controlled and regulated with a set of electrical signals that duplicate, or are similar to the natural electrical messages that have been in existence from the beginning of mammalian life. There are signals that require organs to do their job and also signals that report to the brain with a sort of status report as to how well functionality was happening. In fact the brain does coordinate all of the organs simultaneously and confirm that body homeostasis (life equilibrium) is in good order. The cell or cancer cell also has a sort of feed-back mechanism to insure that metabolism, cell transport of food through the plasma membrane, as well as the excretion of cellular waste along with reproduction, metastatic cell release and movement of organelles within the cytoplasm could also be regulated in accord with a sort of grand operational plan. Cells do not have a brain but they do have sensors and feedback mechanisms that provide a simple awareness to the cell and allow for decision processes. The cellular signals exist as sets of instructions and status massages to maintain cellular homeostasis.